JP7275444B2 - Thieno[2,3-c]pyridazin-4(1H)-one derivative and use thereof - Google Patents

Description

The present invention relates to thieno[2,3-c]pyridazin-4(1H)-one derivatives as ACC1 and ACC2 inhibitors and their use in the manufacture of medicaments as ACC1 and ACC2 inhibitors. Specifically, it relates to a compound represented by formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.

This application is based on Chinese patent application CN201810570719.7 filed on June 5, 2018 and Chinese patent application CN201811033469.7 filed on September 5, 2018. Request priority for X.

Disorders of fatty acid metabolism caused by increased fatty acid synthesis, decreased fatty acid oxidation, or both, include insulin resistance, hepatic steatosis, dyslipidemia, obesity, metabolic syndrome (MetSyn), non-alcoholic fatty liver, etc. It is a sign of a serious metabolic disorder. At the same time, it can lead to the development of type 2 diabetes (T2DM) and vascular diseases such as non-alcoholic steatohepatitis (NASH), atherosclerosis. Since impaired fatty acid metabolism is also one of the hallmarks of cancer and can lead to abnormal and persistent malignant cell growth, inhibiting the synthesis of fatty acids and/or stimulating the oxidative metabolism of fatty acids is It may be beneficial for these diseases (PNAS, 2016, E1796-E1805).

Acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA to malonyl-CoA, which is both the first and pacing step in fatty acid synthesis. ACC has two subtypes, ACC1 and ACC2. ACC1 is mainly distributed in liver and adipose tissue, and ACC2 is mainly distributed in liver, heart and muscle tissue. In the liver, malonyl-CoA catalyzed by ACC1 in the cytoplasm is primarily involved in fatty acid synthesis and elongation; Regulates oxidative metabolism (PNAS, 2016, E1796-E1805). Therefore, simultaneous inhibition of the two subtypes of ACC can both reduce fatty acid synthesis and stimulate oxidative metabolism of fatty acids.

WO2013071169A1 discloses the use of ACC inhibitor I-1811 in the treatment of related diseases.

The present invention provides a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof,

wherein D ₁ is selected from -O- and -N(R ₆ )-;
R ₁ is selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, wherein said C _1-3 alkyl is optionally substituted with 1, 2 or 3 R _a be;

R ₂ is selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1, 2 or 3 R _b be;

R ₃ is selected from H, F, Cl, Br, I and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1, 2 or 3 R _c ;

Alternatively, R ₂ and R ₃ are joined together to form a ring, the ring being selected from C _3-7 cycloalkyl and 4-7 membered heterocycloalkyl, wherein said C _3-7 alkyl and 4- 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R _d ;

R ₄ is selected from OH, NH ₂ , C _1-3 alkyl and C _1-3 alkylamino, wherein said C _1-3 alkyl and C _1-3 alkylamino are 1, 2 or 3 optionally substituted with _Re ;

R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, and C _{1 -6} alkoxy, wherein said C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkoxy are optionally substituted with 1, 2 or 3 R _f ;

R ₆ is H, C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O)-, C _1-6 alkyl-S(=O) ₂ - and C _1-6 alkyl-OC(=O)-, wherein said C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S( =O)-, C _1-6 alkyl-S(=O) ₂ - and C _1-6 alkyl-OC(=O)- optionally substituted with R _g ;

R _a , R _b , R _c , R _d , R _e , R _f and R _g are each independently selected from F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, wherein said C _1-3 alkyl is optionally substituted with 1, 2 or 3 R;
each R is independently selected from F, Cl, Br, I, OH and _NH2 ;

said 4- to 7-membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;

Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form.

In some embodiments of the present invention, said Ra, _Rb , _Rc , _Rd , _Re and _Rf are each independently selected from F, Cl, Br, _I , OH and _NH2 ; The variables of are as defined in the present invention.

In some embodiments of the invention, said _R1 is selected from H, F, Cl, Br, I, OH, _NH2 and _CH3 , the other variables being as defined herein.

In some embodiments of the invention, said _R2 is selected from H, F, Cl, Br, I, OH, _NH2 , _CH3 and Et, the other variables being as defined herein. be.

In some embodiments of the invention, said _R3 is selected from H, F, Cl, Br, I, _CH3 and Et, the other variables being as defined herein.

In some embodiments of the present invention, said R ₂ and R ₃ are joined together to form a ring, said ring being selected from C _3-6 cycloalkyl and 5-6 membered heterocycloalkyl; Said C _3-6 cycloalkyl and 5-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R _d and other variables are _as defined herein.

In some embodiments of the present invention, said R ₂ and R ₃ are joined together to form a ring, which ring consists of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. selected wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl are optionally substituted with 1, 2 or 3 R _d and R _d and other variables are as defined in

In some embodiments of the present invention, said R ₂ and R ₃ are joined together to form a ring, said ring comprising

から選択され、他の変数は、本発明で定義される通りである。

and the other variables are as defined in the present invention.

In some embodiments of the invention, said _R4 is selected from OH and _NH2 , the other variables being as defined herein.

In some embodiments of the present invention, said R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl , C _1-3 alkylamino and C _1-3 alkoxy, wherein said C _1-3 alkyl, C _1-3 alkylamino and C _1-3 alkoxy are 1, 2 or 3 R _f Optionally substituted, R _f and other variables are as defined herein.

In some embodiments of the present invention, said _R51 , _R52 , _R53 , _R54 and _R55 are each independently H, F, Cl, Br, I, OH, _NH2 , _CH3 , Et and

から選択され、他の変数は、本発明で定義される通りである。

and the other variables are as defined in the present invention.

In some embodiments of the present invention, said R ₆ is H, C _1-3 alkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O)-, C _{1 -3} alkyl-S(=O) ₂ - and C _1-4 alkyl-OC(=O)-, wherein said C _1-3 alkyl, C _1-3 alkyl-C(=O )-, C _1-3 alkyl-S(=O)-, C _1-3 alkyl-S(=O) ₂ - and C _1-4 alkyl-OC(=O)- are R _g optionally Substituted, R _g and other variables are as defined in the present invention.

In some embodiments of the present invention, said R ₆ is H, CH ₃ , CH ₃ -C(=O)-, CH ₃ -S(=O) ₂ -, CH ₃ -OC(=O) -as well as

から選択され、他の変数は、本発明で定義される通りである。

and the other variables are as defined in the present invention.

The present invention further provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,

wherein R ₁ is selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, wherein said C _1-3 alkyl _is arbitrarily substituted;

R ₂ is selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1, 2 or 3 R _b be;

R ₃ is selected from H, F, Cl, Br, I and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1, 2 or 3 R _c ;

Alternatively, R ₂ and R ₃ are joined together to form a ring, the ring being selected from C _3-7 cycloalkyl and 4-7 membered heterocycloalkyl, wherein said C _3-7 alkyl and 4- 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R _d ;

R ₄ is selected from OH, NH ₂ , C _1-3 alkyl and C _1-3 alkylamino, wherein said C _1-3 alkyl and C _1-3 alkylamino are 1, 2 or 3 optionally substituted with _Re ;

R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, and C _{1 -6} alkoxy, wherein said C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkoxy are optionally substituted with 1, 2 or 3 R _f ;

R _a , R _b , R _c , R _d , R _e and R _f are each independently selected from F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, wherein said C _{1 -3} alkyl optionally substituted with 1, 2 or 3 R;
each R is independently selected from F, Cl, Br, I, OH and _NH2 ;

said 4- to 7-membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form.

In some embodiments of the present invention, said Ra, _Rb , _Rc , _Rd , _Re and _Rf are each independently selected from F, Cl, Br, _I , OH and _NH2 ; The variables of are as defined in the present invention.

In some embodiments of the invention, said _R1 is selected from H, F, Cl, Br, I, OH, _NH2 and _CH3 , the other variables being as defined herein.

In some embodiments of the invention, said _R2 is selected from H, F, Cl, Br, I, OH, _NH2 , _CH3 and Et, the other variables being as defined herein. be.

In some embodiments of the invention, said _R3 is selected from H, F, Cl, Br, I, _CH3 and Et, the other variables being as defined herein.

In some embodiments of the present invention, said R ₂ and R ₃ are joined together to form a ring, said ring being selected from C _3-6 cycloalkyl and 5-6 membered heterocycloalkyl; Said C _3-6 cycloalkyl and 5-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R _d and other variables are as defined herein.

In some embodiments of the present invention, said R ₂ and R ₃ are joined together to form a ring, said ring consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl. selected wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl are optionally substituted with 1, 2 or 3 R _d and the other variables are defined herein as it is.

In some embodiments of the present invention, said R ₂ and R ₃ are joined together to form a ring, said ring comprising

から選択され、他の変数は、本発明で定義される通りである。

and the other variables are as defined in the present invention.

In some embodiments of the invention, said _R4 is selected from OH and _NH2 , the other variables being as defined herein.

In some embodiments of the present invention, said R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl , C _1-3 alkylamino and C _1-3 alkoxy, wherein said C _1-3 alkyl, C _1-3 alkylamino and C _1-3 alkoxy are 1, 2 or 3 R _f Optional substitutions and other variables are as defined in the present invention.

In some embodiments of the present invention, said _R51 , _R52 , _R53 , _R54 and _R55 are each independently H, F, Cl, Br, I, OH, _NH2 , _CH3 , Et and

から選択され、他の変数は、本発明で定義される通りである。

and the other variables are as defined in the present invention.

Some embodiments of the invention consist of any combination of the above variables.
In some embodiments of the invention, the compound, isomer thereof, or pharmaceutically acceptable salt thereof is selected from

ここで、Ｒ_１、Ｒ_４、Ｒ_５１、Ｒ_５２、Ｒ_５３、Ｒ_５４、Ｒ_５５及びＲ_６は本発明で定義される通りであり；
「＊」が付いた炭素原子はキラル炭素原子であり、（Ｒ）又は（Ｓ）の単一のエナンチオマー又は１つのエナンチオマーに富んだ形で存在する。

wherein R ₁ , R ₄ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ and R ₆ are as defined in the present invention;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form.

In some embodiments of the invention, the compound, isomer thereof, or pharmaceutically acceptable salt thereof is selected from

ここで、ｍは０、１、２又は３であり；
Ｅ_１は－Ｏ－又は－ＮＨ－であり；

wherein m is 0, 1, 2 or 3;
E ₁ is -O- or -NH-;

R ₁ , R ₄ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are as defined herein;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form.

In some embodiments of the invention, the compound, isomer thereof, or pharmaceutically acceptable salt thereof is selected from

ここでＲ_１、Ｒ_４、Ｒ_５１、Ｒ_５２、Ｒ_５３、Ｒ_５４及びＲ_５５は本発明で定義される通りであり；
「＊」が付いた炭素原子はキラル炭素原子であり、（Ｒ）又は（Ｓ）の単一のエナンチオマー又は１つのエナンチオマーに富んだ形で存在する。

wherein R ₁ , R ₄ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are as defined in the present invention;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form.

The present invention further provides a compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the compound, its isomers, or pharmaceutically acceptable salts consist of:

The present invention further provides the use of said compound, its isomers or pharmaceutically acceptable salts in the manufacture of a medicament as an ACC1 and ACC2 inhibitor.
[Technical effect]

As novel ACC1 and ACC2 inhibitors, the compounds of the present invention have potent inhibitory activity against the human ACC1/ACC2 enzymes; greatly enhanced plasma exposure compared to the control compound I-181 . At the same time, the compounds of the invention have good anti-NASH and anti-fibrotic effects.
[Definition and explanation]

Unless otherwise stated, the following terms and collocations used herein have the following meanings. A single specific term or collocation is to be understood as a general definition, not vague or vague, unless specifically defined. When a trade name appears in this specification, it refers to the corresponding trade product or its active ingredients.
As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and that are suitable for use in contact with tissues of the body, without significant undue toxicity, irritation, allergic reactions or other problems or complications, meeting a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of this invention, prepared with relatively non-toxic acids or bases and compounds having certain substituents discovered in this invention. When the compounds of this invention contain relatively acidic functional groups, base addition salts are formed by contacting the neutral forms of these compounds with a sufficient amount of base in solution or a suitable inert solvent alone. Obtainable. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, the acid addition salts are formed by contacting the neutral forms of these compounds with a sufficient amount of acid in solution or in a suitable inert solvent alone. can be obtained. Examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid; The above organic Acids are for example acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid. , including similar acids such as tartaric acid and methanesulfonic acid. Certain specific compounds of the present invention contain basic and acidic functionalities and, therefore, are capable of being converted into any base or acid addition salt.

The pharmaceutically acceptable salts of the invention can be synthesized by conventional methods from parent compounds containing an acid or basic group. Usually, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

Compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- All such mixtures are included within the scope of the present invention, including the isomers, (L)-isomers, and racemic mixtures thereof as well as other mixtures, such as mixtures enriched in enantiomers or non-enantiomers. Other asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and mixtures thereof are included within the scope of this invention.

Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.

Unless otherwise stated, the terms "cis-trans isomer" or "geometric isomer" are due to the inability of a double bond or a single ring carbon atom to rotate freely.

Unless otherwise stated, the term "diastereomers" refers to stereoisomers whose molecules possess two or more chiral centers and which are non-mirror images of each other.

Unless otherwise stated, "(D)" or "(+)" is dextrorotatory, "(L)" or "(-)" is levorotatory, and "(DL)" or "(±)" is racemic. represents

Unless otherwise stated, double bond structures such as carbon-carbon double bonds, carbon-nitrogen double bonds and nitrogen-nitrogen double bonds are present in the compound, and each atom of the double bond has two If two different substituents are attached (for a double bond involving a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered the attached substituent), then on the double bond of the compound Atoms and their substituents are dashed

で連結している場合、当該化合物の（Ｚ）形異性体、（Ｅ）形異性体、又は２つの異性体の混合物を意味する。例えば、下記の式（Ａ）は、当該化合物が式（Ａ－１）又は式（Ａ－２）の単一の異性体の形で存在するか、又は式（Ａ－１）と式（Ａ－２）の２つの異性体の形で存在することを意味し；下記の式（Ｂ）は、当該化合物が式（Ｂ－１）又は式（Ｂ－２）の単一の異性体の形で存在するか、又は式（Ｂ－１）と式（Ｂ－２）の２つの異性体の形で存在することを意味する。下記の式（Ｃ）は、当該化合物が式（Ｃ－１）又は式（Ｃ－２）の単一の異性体の形で存在するか、又は式（Ｃ－１）と式（Ｃ－２）の２つの異性体の形で存在することを意味する。

means the (Z) isomer, the (E) isomer, or a mixture of the two isomers of the compound. For example, formula (A) below indicates whether the compound exists in the form of a single isomer of formula (A-1) or formula (A-2), or formula (A-1) and formula (A-2) -2); formula (B) below means that the compound is in the form of a single isomer of formula (B-1) or formula (B-2). or in two isomeric forms of formula (B-1) and formula (B-2). Formula (C) below indicates whether the compound exists in the form of a single isomer of formula (C-1) or formula (C-2), or ) exists in two isomeric forms.

Certain compounds of the present invention may be present. Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to the fact that isomers of different functional groups are in dynamic equilibrium at room temperature and can be rapidly converted into each other. Tautomers are allowed to reach a chemical equilibrium of tautomers whenever possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers involve interconversions due to rearrangements of some of the bonding electrons. Within, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one. .

Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enriched in an enantiomer" refer to The content of one isomer or enantiomer in is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99 .9% or more.

Unless otherwise stated, the terms "isomeric excess" or "enantiomeric excess" refer to the relative percentage difference value between two isomers or two enantiomers. For example, if one isomer or enantiomer content is 90% and the other isomer or enantiomer content is 10%, the isomer or enantiomer excess (ee value) is 80%. .

Optically active (R)- and (S)- and D- and L-isomers may be prepared using chiral synthesis or chiral reagents or other conventional techniques. To obtain one enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and aided. Cleavage of the group provides the pure desired enantiomer. Alternatively, if the molecule contains basic functional groups (e.g., amino groups) or acidic functional groups (e.g., carboxy groups), diastereomeric salts may be formed with suitable optically active acids or bases, as further known in the art. After separation of the diastereomers by the usual methods of , they are recovered to give the isolated enantiomers. Separation of enantiomers and diastereomers is also usually carried out by chromatographic methods, said chromatographic methods using chiral stationary phases and optionally chemical derivatization methods (e.g. formation of carbamates from amines). Combined. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, compounds can be labeled with radioisotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). Also, for example, hydrogen can be replaced with deuterium to form a deuterated drug, where the bond between deuterium and carbon is stronger than the bond between hydrogen and carbon, and compared to the undeuterated drug, Deuterated drugs have advantages such as reduced toxicity and side effects, increased drug stability, enhanced therapeutic effect, and extended biological half-life of drugs. All isotopic constitutional variations of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"Optional" or "optionally" means that the items or circumstances set forth below may, but do not necessarily, occur, and such statements shall be used only when the items or circumstances described therein occur and when such items or circumstances occur. It is meant to include cases where there is none.
The term "substituted" means that any one or more hydrogen atoms in a specific atom are replaced with a substituent so that the valence state of the specific atom is normal and the compound after substitution is stable. Deuterium and hydrogen variants may also be included, if available. When a substituent is oxo (ie, =O), it means that 2 hydrogen atoms have been replaced. Oxygen substitution does not occur in aromatic groups. The term "optionally substituted" refers to the ability to be substituted or unsubstituted, and unless otherwise defined, the type and number of substituents is any chemically feasible.

When any variable (eg R) occurs more than once in the composition or structure of a compound, its definition is independent in each case. So, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and in each case R has independent choices. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

When the number of linking groups is 0, -(CRR) ₀ -, for example, means that the linking group is a single bond.
When one of the variables is selected from a single bond, it indicates that the two groups it connects are directly linked, for example when L in ALZ represents a single bond, this structure actually becomes AZ.

The absence of one substituent indicates the absence of that substituent, eg, the absence of X in AX indicates that the structure is actually A. Unless it is specified through which atom for a named substituent the substituent is attached to the substituted group, such substituents may be attached through any atom thereof, for example the pyridyl group has pyridine as the substituent It may be attached to a substituted group through any of the carbon atoms in the ring.

Unless otherwise defined, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing a heteroatom) and includes atoms other than carbon (C) and hydrogen (H) and these heteroatoms. Including containing atomic groups such as oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S- , -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and optionally substituted -C (=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)- include.

Unless otherwise defined, the term “alkyl” represents a straight or branched chain saturated hydrocarbon group, in some embodiments said alkyl is C _1-12 alkyl, in other embodiments Said alkyl is C _1-6 alkyl, and in some other embodiments said alkyl is C _1-3 alkyl. It may be monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine). Examples of alkyl are methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (n-pentyl , isopentyl and neopentyl), hexyl, and the like.

Unless otherwise defined, _the term "alkoxy" represents alkyl as _defined above with the specified number of carbon atoms linked through an oxygen bridge _; Including _C3 , _C4 , _C5 and _C6 alkoxy. In some embodiments, said alkoxy is C _1-3 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy and S-pentoxy.

Unless otherwise defined, "cycloalkyl" includes any stable cyclic alkyl, including monocyclic, bicyclic or tricyclic ring systems, where bicyclic and tricyclic ring systems are spiro rings, fused rings and bridged Contains rings. In some embodiments, said cycloalkyl is C _3-8 cycloalkyl, in other embodiments said cycloalkyl is C _3-6 cycloalkyl, and in some embodiments said cycloalkyl Alkyl is C _5-6 cycloalkyl. It may be monovalent, divalent or polyvalent. Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornanyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like. not.

Unless otherwise defined, the term "heterocycloalkyl" by itself or taken together with other terms each denotes a cyclized "heteroalkyl", which includes mono-, bi- and tricyclic ring systems, wherein two Rings and tricyclic ring systems include spiro rings, fused rings and bridged rings. Also, for such "heterocycloalkyl," a heteroatom can occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. In some embodiments, said heterocycloalkyl is a 4-6 membered heterocycloalkyl, and in other embodiments, said heterocycloalkyl is a 5-6 membered heterocycloalkyl. Examples of heterocycloalkyl are azetidinyl, oxetanyl, thietanyl, pyrrolidyl, pyrazolinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuryl (tetrahydrofuran-2-yl, etc.). ), tetrahydropyranyl, piperidyl (including 1-piperidyl, 2-piperidyl and 3-piperidyl, etc.), piperazyl (including 1-piperazyl and 2-piperazyl, etc.), morpholyl (including 3-morpholyl and 4-morpholyl, etc.) ), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazyl, homopiperidinyl and oxepanyl. .

The compounds of the present invention can be made by a variety of synthetic methods familiar to those of skill in the art, including the specific embodiments listed below, embodiments in conjunction with other chemical synthetic methods, and equivalent methods familiar to those of skill in the art. Preferred embodiments include, but are not limited to, examples of the present invention, including alternative methods.

Solvents used in the present invention are commercially available. The present invention uses the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; BOC represents t-butoxycarbonyl, a type of amine protecting group; HOAc represents acetic acid; t. THF represents tetrahydrofuran; BoC ₂ O represents di-tert-butyl dicarbonate TFA represents trifluoroacetic acid; mp represents melting point; CHLOROFORM-d represents deuterated chloroform; DMAP stands for dimethylaminopyridine; EDTA- _K2 stands for ethylenediaminetetraacetic acid dipotassium salt; PEG400 stands for polyethylene glycol 400; DBU stands for 1,8 _- diazabicycloundec-7-ene; NBS represents N-bromosuccinimide; LiHMDS represents lithium hexamethyldisilazide; BPO represents benzoyl peroxide; SEM-Cl represents 2-(trimethylsilyl)ethoxymethyl chloride. MsCl represents methanesulfonyl chloride; TBAF represents tetrabutylammonium fluoride.

Compounds are named artificially or by ChemDraw ^™ ; commercial compounds use the manufacturer's catalog name.

EXAMPLES The present invention will be described in detail below with reference to Examples, which are not intended to limit the scope of the present invention. This specification describes the invention in detail and also discloses specific embodiments thereof, and various modifications and improvements can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. It will be clear to those skilled in the art that

Step 1: Synthesis of compound BB-1-2 Compound BB-1-1 (25 g, 254.67 mmol) was dissolved in dichloromethane (60 mL), and sulfonyl chloride (43 mL, 430.10 mmol) was dissolved in dichloromethane (10 mL) at 0°C. The solution was added dropwise and stirred overnight at room temperature. After the reaction was completed, the solvent was removed under reduced pressure to obtain the crude product BB-1-2, which was directly used in the next step. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] 6.62 (s, 1H), 2.14 (s, 3H).

Step 2: Synthesis of compound BB-1-3 Compound BB-1-2 (40.1 g, 240.04 mmol) was dissolved in chloroform (300 mL) and acetyl chloride (34.3 mL, 480.65 mmol) was added at 0°C. and aluminum trichloride (38.4 g, 287.98 mmol) were added and stirred overnight at room temperature. After completion of the reaction, the reaction solution was poured into ice water (1000 mL), stirred at room temperature for 30 minutes, and extracted with ethyl acetate (500 mL×2). The combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give BB-1-3. rice field. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] 2.64 (s, 3H), 2.26 (s, 3H).

Step 3: Synthesis of Compound BB-1-4 Under an atmosphere of nitrogen gas, sodium hydride ((12.7 g, 60% dispersed in mineral oil, 317.53 mmol) was added to toluene (200 mL), Dimethyl carbonate (17.9 mL, 212.63 mmol) was added to the medium, the temperature was raised to 120° C., and a toluene (50 mL) solution of compound BB-1-3 (22.2 g, 106.17 mmol) was added dropwise for 30 minutes. The reaction was continued for 30 minutes.After completion of the reaction, the aqueous phase was quenched with water (300 mL), and the resulting aqueous phase was extracted with ethyl acetate (150 mL x 2).The combined organic phase was combined with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, solvent removed under reduced pressure _and the residue purified by column chromatography to give BB- ^1-4 . ) δ 12.13 (s, 1H), 5.28 (s, 1H), 3.78 (s, 3H), 2.10 (s, 3H).

Step 4: Synthesis of Compound BB-1-5 Compound BB-1-4 (4.7 g, 17.59 mmol) and triethylamine (2.9 mL, 20.84 mmol) were added to acetonitrile (50 mL) and stirred at 0°C. -Toluenesulfonyl azide (4.2 g, 21.30 mmol) was added and reacted at this temperature for 30 minutes, then at room temperature for 2 hours. After completion of the reaction, it was quenched with water (50 mL) at 0° C., and the obtained aqueous phase was extracted with ethyl acetate (25 mL×2). The combined organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give BB-1-5 got ^<1> H NMR (40 MHz, _CDCl3 ) [delta] 3.83 (s, 3H), 2.12 (s, 3H).

Step 5: Synthesis of compound BB-1-6 Compound BB-1-5 (22.6 g, 77.10 mmol) was added to isopropyl ether (300 mL) and tributylphosphine (20.9 mL, 84.71 mmol) at 0°C. A solution of n-hexane (30 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain BB-1-6. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] 3.92 (s, 3H), 2.12 (s, 3H).

Step 6: Synthesis of compound BB-1-7 Compound BB-1-6 (20.1 g, 68.10 mmol) was dissolved in dichloromethane (300 mL), Boc ₂ O (17.8 g, 81.56 mmol) and DMAP ( 1.7 g, 13.92 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain BB-1-7. ^<1> H NMR (400 MHz, _CDCl3 ) [delta] 3.93 (s, 3H), 2.22 (s, 3H), 1.54 (s, 9H).

Step 7: Synthesis of Compound BB-1 Compound BB-1-7 (26.1 g, 66.03 mmol) was dissolved in DMF (100 mL), K ₂ CO ₃ (10.95 g, 79.24 mmol) was added, The reaction was carried out at 80°C for 12 hours. After completion of the reaction, water (300 mL) and HCl (1M, 100 mL) were added and the resulting aqueous phase was extracted with ethyl acetate (300 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give the desired compound. LCMS: [M+H] ⁺ 258.8.

Step 1: Synthesis of compound BB-2-2 Compound BB-2-1 (4 g, 21.49 mmol) was dissolved in acetonitrile (50 mL) and DBU (4.91 g, 32.23 mmol) and 4-acetamidobenzenesulfonyl azide A solution of (6.19 g, 25.78 mmol) in acetonitrile (10 mL) was added and stirred overnight at room temperature. After completion of the reaction, spin drying was performed under reduced pressure, the solvent was removed, and the residue was separated by column chromatography to obtain the target compound BB-2-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.53 (m, 1H), 7.23-7.20 (m, 1H), 7.12-7.08 (m, 1H), 3.77 (s, 3H).

Step 2: Synthesis of compound BB-2-3 Compound BB-2-2 (0.99 g, 4.67 mmol) and 4-tetrahydropyran (930 μL, 9.29 mmol) were dissolved in dichloromethane (50 mL), and rhodium acetate ( II) Dimer (41 mg, 93 μmol) was added and allowed to react for 5 minutes at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was separated by column chromatography to obtain BB-2-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.47 (m, 1H), 7.10-7.03 (m, 1H), 6.99-6.91 (m, 1H), 5.39 (s, 1H), 3.94-3.81 (m, 2H), 3.66 (s, 3H), 3.59-3.51 (m, 1H), 3.41-3.28 (m , 2H), 1.96-1.87 (m, 1H), 1.83-1.73 (m, 1H), 1.70-1.55 (m, 2H).

Step 3: Synthesis of compound BB-2 Compound BB-2-3 (5.2 g, 18.16 mmol) was dissolved in toluene (100 mL), NaBH ₄ (687 mg, 18.16 mmol) was added at 0°C, and the mixture was stirred at room temperature. for 2 hours. After the reaction was completed, water (50 mL) was added dropwise at 0° C. to quench the reaction, filtered, and the solvent was removed under reduced pressure. Water (50 mL) was added to the residue and extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, spin dried and the resulting residue was separated by column chromatography to give the desired compound BB-2. rice field. ¹ H NMR (40 MHz, CDCl ₃ ) δ 7.52-7.49 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.01 (m, 1H), 5. 05-5.01 (m, 1H), 3.99-3.96 (m, 1H), 3.92-3.90 (m, 1H), 3.72-3.70 (m, 1H), 3.57-3.32 (m, 4H), 2.26-2.23 (m, 1H), 2.05-1.96 (m, 1H), 1.79-1.63 (m, 2H) ), 1.60-1.54 (m, 1H).

Step 1: Synthesis of compound BB-3-2 Compound BB-3-1 (50 g, 277.47 mmol) and NBS (49.39 g, 277.47 mmol) were dissolved in carbon tetrachloride (1 L), and BPO (1. 01 g, 4.16 mmol) was added and reacted at 80° C. for 3 hours. After completion of the reaction, the reaction solution was decompressed to remove the solvent to obtain the target compound BB-3-2, which was directly used in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.61 (m, 1H), 7.37-7.30 (m, 1H), 7.03-6.98 (m, 1H), 6.91 ˜6.88 (m, 1H), 5.91 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H).

Step 2: Synthesis of Compound BB-3-3 Compound BB-3-2 (76.1 g, 293.71 mmol) and 4-tetrahydropyran (58.8 mL, 587.24 mmol) were dissolved in dichloromethane (1.2 L). , silver oxide (68.1 g, 293.87 mmol) was added and stirred at 25° C. for 16 hours. After completion of the reaction, the mixture was filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography to obtain the target compound BB-3-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.43 (m, 1H), 7.35-7.31 (m, 1H), 7.02-7.01 (m, 1H), 6.94 ~6.90 (m, 1H), 5.51 (s, 1H), 4.02-3.92 (m, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 3.65-3.60 (m, 1H), 3.48-3.36 (m, 2H), 2.03-1.94 (m, 1H), 1.92-1.83 (m, 1H) ), 1.79-1.65 (m, 2H).

Step 3: Synthesis of Compound BB-3 Compound BB-3-3 (42.1 g, 150.19 mmol) was dissolved in methanol (300 mL) and NaBH ₄ (28.4 g, 750.94 mmol) was added batchwise at 0°C. was added and allowed to react for 2 hours at room temperature. After completion of the reaction, water (100 mL) was added dropwise at 0° C. to quench, and the solvent was removed under reduced pressure. Water (200 mL) was added to the residue and extracted with dichloromethane (250 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, spin dried and the residue obtained was separated by column chromatography to give the desired compound BB-3. rice field. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.40 (m, 1H), 7.33-7.28 (m, 1H), 7.03-7.00 (m, 1H), 6.94 ~6.85 (m, 1H), 5.11 ~ 5.05 (m, 1H), 4.01 ~ 3.90 (m, 2H), 3.84 (s, 3H), 3.70 ~ 3 .66 (m, 1H), 3.58-3.46 (m, 2H), 3.45-3.33 (m, 2H), 2.38-2.19 (m, 1H), 2.06 ~1.97 (m, 1H), 1.84-1.75 (m, 1H), 1.72-1.60 (m, 2H).

Step 1: Synthesis of compound WX001-1 Compound BB-1 (6.02 g, 23.27 mmol), compound BB-3 (5.87 g, 23.27 mmol) and triphenylphosphine (12.21 g, 46.54 mmol) It was added to tetrahydrofuran (250 mL), DIAD (9.0 mL, 46.29 mmol) was added at 0° C., and reacted at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, the solvent was removed under reduced pressure, and the residue was separated by column chromatography to obtain the target compound WX001-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.54 (m, 1H), 7.38-7.34 (m, 1H), 7.08-7.04 (m, 1H), 6.93 ~6.91 (m, 1H), 5.44 ~ 5.41 (m, 1H), 4.43 ~ 4.39 (m, 1H), 4.17 ~ 4.12 (m, 1H), 4 .01 (s, 3H), 3.90 (s, 3H), 3.73-3.65 (m, 1H), 3.59-3.49 (m, 1H), 3.31-3.28 (m, 1H), 3.27-3.20 (m, 2H), 2.62 (s, 3H), 1.78-1.66 (m, 1H), 1.64-1.48 (m , 2H), 1.29-1.23 (m, 1H).

Step 2: Synthesis of compound WX001-2 NaBH ₄ (1.73 g, 45.64 mmol) was dissolved in methanol (70 mL) and compound WX001-1 (4.5 g, 9.13 mmol) was added batchwise at 0°C. , and 50° C. for 1 hour. The reaction was quenched with water (20 mL) at 0° C., extracted with dichloromethane (25 mL×2), the organic phases were combined and washed with saturated brine (20 mL). Dry over anhydrous sodium sulfate, filter, remove solvent under reduced pressure and use the resulting residue directly in the next step.

Step 3: Synthesis of compound WX001-3 Compound WX001-2 (4.2 g, 9.03 mmol) and phosphorus tribromide (940 μL, 9.90 mmol) were dissolved in DCM (50 mL) under an atmosphere of nitrogen gas, The reaction was allowed to proceed for 30 minutes at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was separated by column chromatography to obtain the desired compound WX001-3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.54 (m, 1H), 7.37-7.33 (m, 1H), 7.07-7.03 (m, 1H), 6.93 ~6.91 (m, 1H), 5.43 ~ 5.40 (m, 1H), 4.64 (d, J = 9.2Hz, 1H), 4.57 (d, J = 9.2Hz, 1H), 4.38-4.33 (m, 1H), 4.07-4.04 (m, 1H), 3.91 (s, 3H), 3.75-3.65 (m, 1H) , 3.63-3.52 (m, 1H), 3.42-3.25 (m, 3H), 2.62 (s, 3H), 1.74-1.64 (m, 1H), 1 .59-1.54 (m, 2H), 1.24-1.20 (m, 1H).

Step 4: Synthesis of compound WX001-4 Compound WX001-3 (3.8 g, 7.20 mmol) was dissolved in DMF (10 mL), KCN (2 g, 30.71 mmol) was added, and reacted at room temperature for 2 hours. . TLC detected raw material still remaining and supplemented with KCN (1.6 g, 24.57 mmol) followed by reaction for 2.5 hours. After the reaction was completed, it was quenched with water (50 mL) at 0° C. and extracted with ethyl acetate (25 mL×2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the resulting residue was separated by column chromatography to obtain the target compound WX001-4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50-7.37 (m, 1H), 7.31-7.22 (m, 1H), 6.98-6.94 (m, 1H), 6.86 ~6.84 (m, 1H), 5.39 ~ 5.36 (m, 1H), 4.41 ~ 4.24 (m, 1H), 4.05 ~ 3.99 (m, 1H), 3 .98-3.75 (m, 5H), 3.74-3.63 (m, 1H), 3.56-3.46 (m, 1H), 3.33-3.29 (m, 1H) , 3.28-3.15 (m, 2H), 2.51 (s, 3H), 1.71-1.61 (m, 1H), 1.59-1.41 (m, 2H), 1 .16-1.04 (m, 1H).

Step 5: Synthesis of compound WX001-5 Compound WX001-4 (2.83 g, 5.97 mmol), 2-(tri-n-butylstannyl)oxazole (5.35 g, 14.93 mmol) in toluene (100 mL) The mixture was dissolved, tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) was added, and the mixture was purged with nitrogen gas three times, then heated to 120° C. and reacted for 1 hour. The reaction was allowed to cool to room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in dichloromethane (30 mL) and quenched with saturated potassium fluoride (30 mL). Extracted with dichloromethane (30 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to obtain the target compound WX001-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 7.48-7.45 (m, 1H), 7.27-7.26 (m, 1H), 7.21 (s, 1H ), 6.99-6.95 (m, 1H), 6.86-6.84 (m, 1H), 5.45-5.41 (m, 1H), 4.42-4.38 (m , 1H), 4.14-4.09 (m, 1H), 3.94-3.82 (m, 5H), 3.71-3.62 (m, 1H), 3.54-3.43 (m, 1H), 3.30-3.35 (m, 1H), 3.27-3.12 (m, 2H), 2.95 (s, 3H), 1.70-1.60 (m , 1H), 1.57-1.47 (m, 2H), 1.12-1.09 (m, 1H).

Step 6: Synthesis of Compound WX001-6 Compound WX001-5 (0.1 g, 197.41 μmol) was dissolved in THF (10 mL), LiHMDS (1 M, 590 μL, 590 μmol) was added dropwise at −65° C., and reacted for 30 minutes. After that, 1,4-dibromobutane (70 μL, 580.32 μmol) was added dropwise and reacted at room temperature for 30 minutes. After the reaction was completed, water (10 mL) was added dropwise to quench at 0°C, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. After filtering to remove the drying agent, the filtrate was decompressed to remove the solvent and separated on a preparative plate to obtain the desired compound WX001-6. LCMS (5-95/1.5 min): 0.973 min, [M+H] ⁺ =561.1.

Step 7: Synthesis of Compound WX001-7 Compound WX001-6 (140 mg, 249.70 μmol) was dissolved in benzyl alcohol (1 mL), and hydrochloric acid 1,4-dioxane solution (4 M, 62 μL, 248 μmol) under nitrogen gas atmosphere. was added and reacted at 50° C. for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was separated by preparative HPLC to obtain the target compound WX001-7 (hydrochloric acid condition). LCMS (5-95/1.5 min): 1.095 min, [M+H] ⁺ =670.1.

Step 8: Synthesis of Compound WX001 Compound WX001-7 (0.14 g, 209.02 μmol) was dissolved in methanol (10 mL), 10% Pd/C (30 mg) was added under an atmosphere of nitrogen gas, and hydrogen gas was added. After substituting with for 3 times, the reaction was carried out at 30° C. for 2 hours under a hydrogen gas atmosphere (30 Psi). The reaction solution was filtered and the solvent was removed under reduced pressure to obtain a residue, which was separated by preparative chromatography (hydrochloric acid conditions) to obtain the target compound WX001. Compound WX001 was subjected to supercritical fluid chromatography (column: Chiralpak AD-3, 100×4.6 mm I.D., 3 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol; gradient : B reaches 5% to 40% within 4.5 min, hold at 40% for 2.5 min, return to 5% and equilibrate for 1 min; flow rate: 2.8 mL/min; column temperature: 40°C; (wavelength: 220 nm) was detected to be a racemate. The chiral isomers WX001A and WX001B were separated and their retention times were 3.954 min and 4.388 min respectively.

Referring to the synthetic method of steps 6-8 of Example 1 and using different halide fragments in step 6, each example in the following table was synthesized. The structures in the table simultaneously represent their possible isomers.

Step 1: Synthesis of Compound WX011-1 Compound BB-1 (20 g, 77.32 mmol) was dissolved in DMF (270 mL) and NaH (4.02 g, 60% dispersed in mineral oil, 100.51 mmol) was added. After stirring at 0° C. for 30 minutes, SEM-Cl (15 mL, 84.75 mmol) was added and allowed to react at room temperature for 1 hour. The reaction was quenched with water (800 mL), extracted with ethyl acetate (400 mL x 2), the combined organic phases were washed with saturated brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered and evaporated. The solvent was removed with , and the resulting residue was separated by column chromatography to obtain the desired compound WX011-1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.52 (s, 2H), 3.99 (s, 3H), 3.66-3.62 (m, 2H) 2.59 (s, 3H), 1.00 ~0.96 (m, 2H), 0.00 (s, 9H).

Step 2: Synthesis of compound WX011-2 Compound WX011-1 (10 g, 25.71 mmol) was dissolved in methanol (100 mL), lithium borohydride (2.8 g, 128.55 mmol) was added, and the mixture was stirred at room temperature for 2 hours. reacted. Quench the reaction with water (200 mL), remove methanol under reduced pressure, extract with ethyl acetate (300 mL x 2), combine the organic phases, wash with saturated brine (50 mL x 2), dry with anhydrous sodium sulfate. Dry, filter, remove solvent under reduced pressure and use the resulting residue directly in the next reaction. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.48 (s, 2H), 4.77 (s, 2H), 3.64-3.60 (m, 2H), 2.58 (s, 3H), 1. 00-0.95 (m, 2H), 0.01 (s, 9H).

Step 3: Synthesis of compound WX011-3 Compound WX011-2 (8 g, 22.16 mmol) and triethylamine (6.2 mL, 44.33 mmol) were dissolved in dichloromethane (100 mL) and mixed with MsCl (2.3 mL, 29 mL) at 0°C. .68 mmol) was added and allowed to react for 1 hour after complete addition. The reaction was quenched with ice water (100 mL), extracted with dichloromethane (60 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue was used directly for the next reaction.

Step 4: Synthesis of compound WX011-4 Compound WX011-3 (8.5 g, 19.36 mmol) was dissolved in DMF (100 mL), NaCN (4.07 g, 83.04 mmol) was added, and reacted at room temperature for 2 hours. let me After the reaction was completed, it was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the resulting residue was separated by column chromatography to yield the desired product. Compound WX011-4 was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.51 (s, 2H), 3.90 (s, 2H), 3.66-3.62 (m, 2H), 2.56 (s, 3H), 0.99-0.95 (m, 2H), 0.00 (s, 9H).

Step 5: Synthesis of compound WX011-5 Compound WX011-4 (2.5 g, 6.76 mmol), 2-(tri-n-butylstannyl)oxazole (6.05 g, 16.89 mmol) in toluene (30 mL) The solution was dissolved, tetrakis(triphenylphosphine)palladium (1.56 g, 1.35 mmol) was added, and after purging with nitrogen gas three times, the temperature was raised to 120° C. and the reaction was allowed to proceed for 4 hours. After cooling to room temperature, quench with saturated potassium fluoride (20 mL), add water (80 mL), extract with ethyl acetate (100 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, Filtration, removal of the solvent under reduced pressure and separation of the residue by column chromatography gave the desired compound WX011-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.29 (s, 1H), 5.60 (s, 2H), 3.94 (s, 2H), 3.71-3. 67 (m, 2H), 3.02 (s, 3H), 1.02-0.98 (m, 2H), 0.01 (s, 9H).

Step 6: Synthesis of Compound WX011-6 Compound WX011-5 (1.9 g, 4.72 mmol) and methyl iodide (1.6 mL, 25.50 mol) were dissolved in THF (20 mL) and potassium tert- A butoxide solution (1 M, 14.2 mL, 14.2 mmol) was added dropwise and allowed to react at room temperature for 1 hour. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 2), combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was evaporated under reduced pressure. Solvent was removed and the resulting residue was used directly for the next reaction. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.29 (s, 1H), 5.54 (s, 2H), 3.70-3.65 (m, 2H), 3. 02 (s, 3H), 1.64 (s, 6H), 1.00-0.96 (m, 2H), 0.01 (s, 9H).

Step 7: Synthesis of Compound WX011-7 Compound WX011-6 (1 g, 2.32 mmol) was added to a THF solution of TBAF (1 M, 15 mL, 15 mmol) and allowed to react at room temperature for 1 hour. After completion of the reaction, quenched with water (80 mL), extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with water (50 mL x 5), dried over anhydrous sodium sulfate, filtered to dryness. The agent was removed, the filtrate was decompressed to remove the solvent, and the resulting residue was used directly in the next reaction. ^<1> H NMR (400 MHz, CDCl3) _[delta ] 7.72 (s, 1H), 7.24 (s, 1H), 2.95 (s, 3H), 1.81 (s, 6H).

Step 8: Synthesis of compound WX011-8 Compound WX011-7 (0.56 g, 1.86 mmol), compound WX011-7a (786 mg, 2.24 mmol) and triphenylphosphine (978 mg, 3.73 mmol) were combined with tetrahydrofuran (10 mL). DIAD (730 μL, 3.75 mmol) was added at 0° C. and reacted at room temperature for 15 hours. After the reaction was completed, the solvent was removed under reduced pressure and the resulting residue was directly used in the next reaction. LCMS: [M+Na] = 656.2.

Step 9: Synthesis of Compound WX011-9 Compound WX011-8 (0.9 g, 1.42 mmol) was dissolved in benzyl alcohol (15 mL) and hydrochloric acid in 1,4-dioxane (4 M, 15 mL) was added. °C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure and the resulting residue was slurried with methyl tert-butyl ether (150 mL) to give the desired compound WX011-9. LCMS: [M+H] ⁺ = 643.4.

Step 10: Synthesis of compound WX011-10 To compound WX011-9 (0.1 g, 155.58 μmol) was added dichloromethane (0.7 mL), sodium hydroxide (1 M, 0.8 mL) was added, and acetyl chloride ( 44 μL, 622 μmol) was added and allowed to react at room temperature for 1 hour. Extracted with dichloromethane (5 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent, after which the filtrate was decompressed to remove the solvent. The resulting residue was separated by preparative chromatography (hydrochloric acid conditions) to obtain the target compound WX011-10. LCMS: [M+H] ⁺ =707.1.

Step 11: Synthesis of compound WX011 Compound WX011-10 (50 mg, 73.01 μmol) was dissolved in methanol (5 mL), 10% Pd/C (100 mg) was added under an atmosphere of nitrogen gas, and hydrogen gas was added for 3 minutes. After being replaced twice, the reaction was carried out at room temperature for 1 hour under a hydrogen gas atmosphere (15 Psi). The reaction solution was filtered and the solvent was removed under reduced pressure to obtain a residue, which was separated by preparative chromatography (hydrochloric acid conditions) to obtain the target compound WX011.

Compound WX011 was subjected to supercritical fluid chromatography (column: (S,S) Whelk-01, 100×4.6 mm ID, 5 μm; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine Methanol solution; Gradient: B from 5% to 40% within 4.5 min, hold at 40% for 2.5 min, return to 5% and equilibrate for 1 min; Flow rate: 2.8 mL/min; Column Temperature: 40°C; Wavelength: 220 nm), it was detected to be a racemic compound. The chiral isomers WX011A and WX011B were separated and their retention times were 3.078 min and 3.734 min, respectively.

WX011A, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.47-7.42 (m, 1H), 7.30-7.26 (m, 2H), 6.99-6 .96 (m, 1H), 6.86-6.84 (m, 1H), 5.47-5.42 (m, 1H), 4.39-4.30 (m, 1H), 4.15 ~4.10 (m, 1H), 3.82 (s, 3H), 3.47-3.00 (m, 5H), 2.95 (s, 3H), 1.93, 1.91 (2s , 3H), 1.54-1.19 (m, 10H); LCMS (5-95 AB/1.5 min): Rt = 0.904; [M+Na] = 617.3.

WX011B, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (s, 1H) 7.47-7.42 (m, 1H) 7.30-7.26 (m, 2H) 6.99-6.96 ( m, 1H) 6.86-6.84 (m, 1H) 5.47-5.42 (m, 1H) 4.39-4.33 (m, 1H) 4.15-4.10 (m, 1H) 3.82 (s, 3H) 3.47-3.00 (m, 5H) 2.95 (s, 3H) 1.93, 1.91 (2s, 3H) 1.54-1.19 ( m, 10H); LCMS (5-95 AB/1.5 min): Rt = 0.904; [M+Na] = 617.4.

Referring to the synthetic method of steps 10, 11 of Example 1 and using different intermediate fragments in step 10, each example in the following table was synthesized. The structures in the table simultaneously represent their possible isomers.

Example 1: In vitro evaluation

Purpose of experiment:
The inhibitory potency of test compounds against acetyl-CoA carboxylase (ACC) is assessed by measuring _IC50 values.

Experiment material:
1. Proteins: human acetyl-CoA carboxylase 1 (hACC1) and human acetyl-CoA carboxylase 2 (hACC2).
2. Substrate: _NaHCO3
3. Cofactor: acetyl coenzyme A, ATP
4. Activator: Potassium Citrate

experimental method:
1. 1x enzyme/substrate/cofactor was added to the wells of the well plate.
2. Compounds in DMSO were added to the enzyme mixture using an acoustic technique and preincubated for 15 minutes.
3. ATP was added to it to initiate the reaction and shaken uniformly.
4. Incubated for 1 hour at room temperature.
5. The reaction was quenched followed by incubation for 40 minutes.
6. Detection reagent was added and incubated for 30 minutes.
7. Fluorescence was tested.
8. Data Analysis: Fluorescence signal was converted to ADP product concentration and enzymatic activity was calculated based on the ADP standard curve. Graphpad Prism software was utilized to fit curves and obtain _IC50 values. The experimental results were as shown in Table 5.

Conclusion: The compounds of the present invention have strong inhibitory activity against human-derived ACC1/ACC2 enzymes.

Experimental Example 2: Pharmacokinetic Evaluation of Compounds

Purpose of experiment:
The pharmacokinetics of test compounds are tested in C57BL/6 mice.

Experiment material:
C57BL/6 mice (male, 18-30 g, 7-9 weeks old, Shanghai Lingchang Biological Technology Co., Ltd.)

Experimental operation:
A clear solution of the test compound (0.5 mg/ml, 10% DMSO, 10% polyethylene glycol stearate, 80% water) was administered intracorporeally to 4 male C57BL/6 mice (overnight fasting, 7-7 days). At 9 weeks of age), the mice were intravenously injected into the tail vein, and the dose was 2.0 mg/kg. A suspension or clear solution of test compound (1 mg/ml, 10% PEG400, 90% (0.5% methylcellulose + 0.2% Tween80)) was administered to 4 male C57BL/6 mice (overnight fasting). and 7-9 weeks old) were administered intragastrically at a dose of 10 mg/kg.

Two mice per group were alternately bled, with each mouse being bled at 4-5 hour time points. 0.0833 h (IV group only), 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h and 24 h after intravenous or intragastric administration of mice Approximately 30 μL of blood was collected by puncturing the saphenous vein, placed in an anticoagulant tube containing EDTA-K2, and plasma was centrifuged. Blood drug concentrations were measured using an LC-MS/MS method and correlated with a log-linear trapezoidal non-compartmental model using WinNonlin ^™ Version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software. Pharmacokinetic parameters were calculated.

The experimental results were as shown in Table 6:

結論：本発明の化合物は、マウスの薬物動態の単一又は部分的な指標を有意に向上させることができる。

Conclusion: The compounds of the present invention can significantly improve single or partial pharmacokinetic measures in mice.

Example 3: In vivo pharmacokinetic study in NASH mouse model induced by HFD + _CCl4

Purpose of experiment:
The purpose of this study was to study the effects of compounds on improving NASH and liver fibrosis in the HFD+CCl ₄ mouse model, using I-181 as a reference compound.

I-181 is an Acetyl-CoA Carboxylases inhibitor currently in Phase II clinical trials for Non Alcoholic Fatty Liver Disease (NAFLD). The HFD + CCl ₄ mouse model used in this study is an animal model that simulates the progression of human non-alcoholic fatty liver disease to NASH, and a high-fat diet causes fat accumulation and degeneration in hepatocytes; CCl ₄ ( intraperitoneal injection, twice a week) simulated a 'second hit' of liver injury. The model is stable and reliable, has high similarity to the pathogenesis of human NASH, and has the main pathological features of NASH such as steatosis, apoptosis, inflammation and fibrosis, as well as plasma transaminases (ALT and AST) levels were also shown.

Experimental design:
The model of this study involved two steps: high-fat diet feeding and _CCl4 induction. were selected to continue to receive a high-fat diet while being injected intraperitoneally twice weekly with 25% CCl ₄ at 0.5 mg/kg for 4 weeks. The day when CCl ₄ administration started was day 0, the time when CCl ₄ administration started was 0 o'clock, the day when CCl ₄ administration started, intragastric administration was started, and the administration volume of each group was 5 mL. /kg once daily for 4 weeks (28 days). Injections of CCl ₄ had to be separated by at least 4 hours from the time of the first administration of the day. The experiment was divided into 6 groups: healthy control group, model group, reference compound group (GS-0976), test compound group (WX004B, 3 doses). The healthy control group consisted of 10 normal mice, fed with normal chow and not injected with _CCl4 during the experimental period; Mice were divided into groups and then injected intraperitoneally with different doses of _CCl4 . Grouping and dose design were as shown in Table 7.

Experimental result:
In mouse models induced by a combination of high fat diet and _CCl4 , WX004B achieved the same effect as the higher dose of the reference compound in both the NAS and fibrosis dimensions.

Claims (20)

A compound of formula (II), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof .

(where D ₁ is selected from -O- and -N(R ₆ )-;
R ₁ is selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, wherein said C _1-3 alkyl is optionally substituted with 1, 2 or 3 R _a be;
R ₂ is selected from H, F, Cl, Br, I, OH, NH ₂ and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1, 2 or 3 R _b be;
R ₃ is selected from H, F, Cl, Br, I and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1, 2 or 3 R _c ;
Alternatively, R ₂ and R ₃ are joined together to form a ring, the ring being selected from C _3-7 cycloalkyl and 4-7 membered heterocycloalkyl, wherein said C _3-7 alkyl and 4- 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R _d ;
R ₄ is selected from OH, NH ₂ , C _1-3 alkyl and C _1-3 alkylamino, wherein said C _1-3 alkyl and C _1-3 alkylamino are 1, 2 or 3 R _e optionally replaced by;
R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, and C _{1 -6} alkoxy, wherein said C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkoxy are optionally substituted with 1, 2 or 3 R _f ;
R ₆ is H, C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O)-, C _1-6 alkyl-S(=O) ₂ - and C _1-6 alkyl-OC(=O)-, wherein said C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S( =O)-, C _1-6 alkyl-S(=O) ₂ - and C _1-6 alkyl-OC(=O)- optionally substituted with R _g ;
R _a , R _b , R _c , R _d , R _e , R _f and R _g are each independently selected from F, Cl, Br, I, OH, NH ₂ and C _1-3 alkyl, wherein said C _1-3 alkyl is optionally substituted with 1, 2 or 3 R;
each R is independently selected from F, Cl, Br, I, OH and _NH2 ;
said 4- to 7-membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form. ) _2. The compound of claim 1, wherein Ra, _Rb , _Rc , _Rd , _Re , _Rf and _Rg are each independently selected from F, Cl, Br, I, OH and _NH2 , a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof ; _3. A compound, stereoisomer thereof, tautomer thereof , or thereof according to claim 1 or 2, wherein R1 is selected from H, F, Cl, Br, I, OH, _NH2 and _CH3. A pharmaceutically acceptable salt of _{3. The} compound _of claim 1 or 2, its stereoisomer , its tautomer, or its pharmaceutically acceptable salts thereof . _3. A compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutical compound thereof according to claim 1 or 2, wherein R3 is selected from H, F, Cl, Br, I, _CH3 and Et. permissible salt. R ₂ and R ₃ are joined together to form a ring, which ring is selected from C _3-6 cycloalkyl and 5-6 membered heterocycloalkyl, said C _3-6 cycloalkyl and 5-6 3. A compound, a _stereoisomer thereof, a tautomer thereof , or a pharmaceutically acceptable salt. R ₂ and R ₃ are linked together to form a ring, which ring is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl, wherein said cyclopropyl, cyclobutyl 7. The _compound of claim 6, a stereoisomer thereof, a tautomer thereof, or pharmaceutically acceptable salts thereof . R ₂ and R ₃ are linked together to form a ring, which ring is

8. The compound of claim 7, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof , selected from: 3. The compound of claim 1 or 2, a stereoisomer thereof, a tautomer thereof , or a pharmaceutically acceptable salt thereof , wherein _R4 is selected from OH and _NH2 . R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are each independently H, F, Cl, Br, I, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkylamino and C _{1- 3} alkoxy, wherein said C _1-3 alkyl, C _1-3 alkylamino and C _1-3 alkoxy are optionally substituted with 1, 2 or 3 R _f A compound, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof according to . _R51 , _R52 , _R53 , _R54 and _R55 are each independently H, F, Cl, Br, I, OH, _NH2 , _CH3 , Et and

11. The compound of claim 10, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof , selected from: R ₆ is H, C _1-3 alkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O)-, C _1-3 alkyl-S(=O) ₂ - and C _1-4 alkyl-OC(=O)-, wherein said C _1-3 alkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S( =O)-, C _1-3alkyl -S(=O) ₂ - and C _1-4alkyl -O-C(=O)- are optionally substituted with R _g or a stereoisomer thereof, a tautomer thereof , or a pharmaceutically acceptable salt thereof . R ₆ is H, CH ₃ , CH ₃ -C(=O)-, CH ₃ -S(=O) ₂ -, CH ₃ -OC(=O)- and

13. The compound of claim 12, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof , selected from: 14. A compound according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein the compound is selected from:

(wherein R ₁ is as defined in claim 1 or 3;
R ₄ is as defined in claim 1 or 9;
_R51 , _R52 , _R53 , _R54 and _R55 are as defined in claim 1, 10 or 11;
R ₆ is as defined in claim 1, 12 or 13;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form. ) 15. The compound according to Claim 14, wherein the compound is selected from a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof .

(where m is 0, 1, 2 or 3;
E ₁ is -O- or -NH-;
R ₁ is as defined in claim 1 or 3;
R ₄ is as defined in claim 1 or 9;
_R51 , _R52 , _R53 , _R54 and _R55 are as defined in claim 1, 10 or 11;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form. ) 16. The compound of Claim 15, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein the compound is selected from:

(wherein R ₁ , R ₄ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ and R ₅₅ are as defined in claim 15;
Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which exist in single (R) or (S) enantiomers or in one enantiomer-enriched form. ) A compound of the formula below, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof .

18. The compound according to claim 17, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof , represented by the following chemical structural formula .

A compound according to any one of claims 1 to 18, its stereoisomer , its tautomer, or a pharmaceutically acceptable salt thereof , in the manufacture of a medicament as an ACC1 and ACC2 inhibitor. Use of. A compound according to any one of claims 1 to 18, its stereoisomers, its tautomers, in the manufacture of a medicament as a therapeutic agent for non-alcoholic steatohepatitis and liver fibrosis, or use of pharmaceutically acceptable salts thereof.